竹节参皂苷IVa通过IRS-2/Akt/GSK-3β信号通路介导胰岛β细胞损伤的保护作用及机制

胰岛β细胞功能减退和数量减少在糖尿病的发病和进展中都具有重要的作用，如何保护胰岛β细胞一直是2型糖尿病研究和治疗的关键。我们前期研究表明，楤木皂苷抗2型糖尿病和胰岛保护效果明确，其活性成分竹节参皂苷IVa（CHS）可明显促进胰岛素释放，增加神经细胞GSK-3β磷酸化水平，预实验结果表明，CHS可显著减少胰岛β细胞凋亡，但其具体作用机制仍不清楚。近年来的研究表明，GSK-3β作为发挥胰岛素功能的主要信号通路IRS-2/Akt的下游分子，在维持胰岛β细胞的数量，增加胰岛素分泌中发挥着关键性的作用。本课题拟在前期研究基础之上，进一步深入考察CHS对胰岛β细胞损伤的保护作用及其分子机制，尤其是IRS-2/Akt/GSK-3β在其中的关键作用。阐明这一问题，不仅可以揭示CHS保护胰岛β细胞的作用机制，还可以优化药物结构，为此类抗糖尿病药物的研究奠定基础，具有重要的理论和临床价值。

Pancreatic β-cell dysfunction and depletion in numbers are necessary in the onset and development of type 2 diabetes. Thus, protecting pancreatic β cells is always the key to the treatment of type 2 diabetes. Our previous studies showed that the total saponin extract of Aralia taibaiensis exhibited excellent insulinogenic and antidiabetic activites, and its active constitutent Chikusetsu saponin IVa (CHS) could induced insulin secretion obviously, and strengthen the phosphorylation level of GSK-3β in nerve cells. The pilot experiments showed that CHS decreased apoptosis and increased the number of β cells. However, the mechanisms of these protective are largely unclear. Recent studies suggested that GSK-3β as the downstream of the main insulin function signal pathway IRS-2/Akt, plays an important role in maintaining the number of pancreatic β cells and regulating the secretion of insulin. On the basis of our previous researches, we propose to further study the protective effect of CHS on pancreatic β-cells and its mechanism, specifically the key role of IRS-2/Akt/GSK-3β pathway. These studies not only reveal the mechanisms of CHS but also useful in the structure optimization and provide a theoretical foundation of such drugs for the treatment of diabetes, which has both theoretical and clinical importance.